We study Salmonella-host interactions and have shown that a host regulator of fatty acid metabolism, PPAR?, controls persistent systemic S. Typhimurium infection in mice. PPAR?, a transcriptional factor that plays a role in regulating metabolic and immune pathways, is specifically upregulated in Salmonella- infected macrophages. Importantly, PPAR?-deficient mice are not chronically infected with S. Typhimurium. The long-term goal of this research proposal is to understand how S. Typhimurium usurps and manipulates host metabolic and immune activities during chronic infection. In Aim 1, we will use genetic and biochemical approaches to identify mechanisms of Salmonella-dependent activation of PPAR?. In Aim 2, we will identify the PPAR?-dependent immune and metabolic pathways required for Salmonella replication in macrophages. In Aim 3, we will use germ-free mice and mice deficient for PPAR? in macrophages or gut epithelial cells to characterize PPAR?-dependent mechanisms of Salmonella persistence in the gastrointestinal tract. These studies are aimed at gaining a better understanding of the molecular mechanisms of host-pathogen interactions during chronic infections, which will lead to the rational design of therapeutics that will benefit public health.